The present invention relates to a novel method for solid phase synthesis of diverse sulfonamido amide, carboxylic acid and hydroxamic acid derivatives, and the use of such a method to create combinatorial libraries of diverse sulfonamido amides, carboxylic acids and hydroxamic acids.
Sulfonamido carboxylic acids and their derivatives are widely used as building blocks in the design and synthesis of biologically active peptidomimetics, such as sulfonamide peptoids. xcex1-Sulfonamido carboxylic acids and the corresponding hydroxamic acid derivatives are also an important class of matrix metalloprotease inhibitors which have recently received great attention as therapeutic agents for the treatment of human diseases. Several xcex1-sulfonamido hydroxamic acids are currently under clinical investigation against arthritis and cancer.
Conventional approaches to the preparation of the sulfonamido acid derivatives rely on the use of amino acids as the starting material followed by N-sulfonylation. However, the process can be tedious if the amino acids to be used are not readily available although a great deal of efforts have been made during the last three decades in the development of efficient methods for the synthesis of unnatural amino acid derivatives.
Based on the usefulness of the above-described compounds, if would generally be advantageous to have methods of rapidly and efficiently synthesizing structurally diverse derivatives of these compounds, as well as libraries containing large numbers of these compounds. The present invention meets these and other needs.
The importance of multi-component reactions (MCR) has been demonstrated in the synthesis of various classes of organic molecules, especially in the area of combinatorial synthesis. These reactions enable to assemble three or more different building blocks, in most cases, in a single chemical process. The Ugi condensation reaction employs four components including a carboxylic acid, an amine, an aldehyde and an isocyanide to construct an xcex1-acylaminoamide which can be transferred into the corresponding amino acid, ester and etc. The versatility of the reaction has also been demonstrated in the solid phase synthesis of a variety of biologically interesting structures by post Ugi transformations.
The methods of the invention employ a multi-component condensation reaction for the construction of the key intermediates on solid supports.
The invention is generally directed to novel methods of synthesizing diverse xcex1-sulfonamido amide, carboxylic acid and hydroxamic acid derivatives. Typically, the methods of the invention employ a multi-component condensation reaction for the construction of the key intermediates on solid supports. Instead of amines (e.g., alkyl amine or aniline), according to the invention sulfonamides are the first time employed in the four-component condensation reaction. This four-component reaction (a sulfonamide, an aldehyde or ketone, an isocyanide and an acid) enables one to generate a sulfonamido amide-type intermediate in one-step on solid support (FIGS. 1 and 2).
Either of the four components can be attached to the solid support, which reacts with other three reagents (FIG. 2). Further chemical manipulation, such as treatment with a base to remove the acyl moiety followed by N-alkylation, such as the Mitsunobu reaction, gives polymer-bound products, which are then cleaved on the solid support under various cleavage conditions.
The present invention also provides methods of preparing libraries of diverse xcex1-sulfonamido amide, carboxylic acid and hydroxamic acid derivatives. The method of synthesizing a library of xcex1-sulfonamido amide, carboxylic acid or hydroxamic acid derivatives comprising providing a set of polymer-bound reactant(s) (sulfonamide, aldehyde or ketone, isocyanide or acid) to react with three sets of the other three reactants to form an array of polymer-bound xcex1-sulfonamido amide-type intermediates. Further chemical manipulation may be applied, which comprises the treatment with a base for removal of the acyl moiety and N-alkylation gives polymer-bound highly functionalized products. A library of the diverse products is then released from the solid support under various cleavage conditions.